Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
NHC Key Laboratory of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, 2140 Xietu Road, Shanghai 200032, China.
Oxid Med Cell Longev. 2023 Feb 9;2023:6935947. doi: 10.1155/2023/6935947. eCollection 2023.
The pathogenesis of Alzheimer's disease (AD) involves multiple pathophysiological processes. Oxidative stress is a major cause of AD-associated neuronal injury. The current research was designed to examine whether a novel (-)-meptazinol-serotonin hybrid (Mep-S) with potent antioxidant activity and additional inhibitory properties for acetylcholinesterase (AChE) activity could attenuate oxidative neuronal damage and cognitive deficits. In human SH-SY5Y cells, Mep-S suppressed HO-induced apoptosis by restoring mitochondrial membrane potential and inhibiting caspase-3 activation. Meanwhile, it attenuated oxidative stress elicited by HO through lessening generation of reactive oxygen species as well as enhancing production of glutathione (GSH) and activity of superoxide dismutase (SOD). Mechanistically, Mep-S promoted nuclear translocation of a transcription factor nuclear factor E2-related factor-2 (Nrf2) in HO-challenged cells. This effect was accompanied by reduction in Kelch-like ECH-associated protein-1 (Keap1) levels as well as augmentation of Akt phosphorylation and expression of heme oxygenase-1 (HO-1) and NAD(P)H quinine oxidoreductase-1 (NQO-1). Molecular docking analysis revealed that Mep-S may disrupt the protein-protein interactions between Keap1 and Nrf2. In an mouse model, Mep-S attenuated scopolamine-caused cognitive deficits with inhibition of apoptotic neuronal death and brain AChE activity. Furthermore, the scopolamine-induced impairment of total antioxidant capacity and reduction in SOD1, SOD2, and -glutamate-cysteine ligase expression in the brain were counteracted by Mep-S, accompanied by decreased Keap1 levels, increased Akt catalytic subunit and Nrf2 phosphorylation, and decreased Nrf2, HO-1, and NQO-1 expression. Collectively, our results suggest that Mep-S ameliorates apoptotic neuronal death and memory dysfunction associated with oxidative stress by regulating the Nrf2/antioxidant enzyme pathway through inactivating Keap1 and phosphorylating Nrf2 via Akt activation. Therefore, Mep-S may be a potential lead for multitarget neuroprotective agents to treat AD-like symptoms.
阿尔茨海默病（AD）的发病机制涉及多种病理生理过程。氧化应激是 AD 相关神经元损伤的主要原因。本研究旨在探讨一种新型（-）-美普他酚-5-羟色胺混合体（Mep-S）是否具有强大的抗氧化活性和对乙酰胆碱酯酶（AChE）活性的抑制作用，能否减轻氧化应激诱导的神经元损伤和认知功能障碍。在人 SH-SY5Y 细胞中，Mep-S 通过恢复线粒体膜电位和抑制半胱天冬酶-3 激活来抑制 HO 诱导的细胞凋亡。同时，它通过减少活性氧的产生以及增强谷胱甘肽（GSH）的产生和超氧化物歧化酶（SOD）的活性来减轻由 HO 引起的氧化应激。在机制上，Mep-S 促进了 HO 处理细胞中转录因子核因子 E2 相关因子 2（Nrf2）的核易位。这一作用伴随着 Kelch 样 ECH 相关蛋白-1（Keap1）水平的降低，以及 Akt 磷酸化和血红素加氧酶-1（HO-1）和 NAD（P）H 醌氧化还原酶-1（NQO-1）表达的增加。分子对接分析表明，Mep-S 可能破坏了 Keap1 和 Nrf2 之间的蛋白质-蛋白质相互作用。在一种 小鼠模型中，Mep-S 抑制了东莨菪碱引起的认知功能障碍，同时抑制了凋亡性神经元死亡和大脑乙酰胆碱酯酶活性。此外，Mep-S 还阻止了东莨菪碱引起的大脑总抗氧化能力的损害以及 SOD1、SOD2 和 -谷氨酰半胱氨酸连接酶表达的减少，同时降低了 Keap1 水平，增加了 Akt 催化亚基和 Nrf2 的磷酸化，降低了 Nrf2、HO-1 和 NQO-1 的表达。综上所述，我们的研究结果表明，Mep-S 通过激活 Akt 使 Keap1 失活并使 Nrf2 磷酸化，从而调节 Nrf2/抗氧化酶途径，减轻与氧化应激相关的凋亡性神经元死亡和记忆功能障碍，可能成为治疗 AD 样症状的多靶点神经保护剂的潜在先导化合物。
